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Induction and Repair of DNA Cross-Links in Chinese Hamster Ovary Cells Treated With Various Platinum Coordination Compounds in Relation to Platinum Binding to DNA, Cytotoxicity, Mutagenicity, and Antitumor Activity

Induction and Repair of DNA Cross-Links in Chinese Hamster Ovary Cells Treated With Various Platinum Coordination Compounds in Relation to Platinum Binding to DNA, Cytotoxicity, Mutagenicity, and Antitumor Activity

A C Plooy, M van Dijk, P H Lohman

Cancer Res. 1984 May;44(5):2043-51.

PMID: 6538808

Abstract:

Several effects of four diamminechloroplatinum compounds (II and IV) in Chinese hamster ovary cells were studied. The two cis-compounds [cis-diamminedichloroplatinum(II) and cis-diamminetetrachloroplatinum(IV)] are known to possess antitumor activity, whereas the two trans-stereoisomers [trans-diamminedichloroplatinum(II) and trans-diamminetetrachloroplatinum(IV)] are inactive. When the effects of the cis-and trans-platinum compounds were compared after treatments that resulted in the binding of equal amounts of platinum to the DNA of the cells, the following differences were found: (a) the cis-platinum adducts gave a much higher cytotoxicity; (b) only the cis-platinum-DNA complexes were strongly mutagenic (forward mutations at the hypoxanthine-guanine phosphoribosyltransferase locus); (c) the cis-platinum adducts induced more sister chromatid exchanges; (d) the cis compounds initially induced fewer DNA-protein cross-links (Factors 5 to 8), but these cis-platinum cross-links were much more persistent; (e) for both cis complexes, the amount of DNA interstrand cross-links passed through a maximum between 6 and 12 hr after treatment, and the cross-links were repaired slowly. One trans-compound [trans-diamminetetrachloroplatinum(IV)] resembled the cis complexes with respect to the overall kinetics of formation and disappearance of this type of lesion, but the repair went faster. For the other trans compound [trans-diamminedichloroplatinum(II)], the highest number of cross-links was detected directly after the treatment of the cells, and they were rapidly eliminated. Neither the number of platinum-DNA lesions as such nor the initial amount of DNA interstrand cross-links could be related to the (geno)toxic effects of the compounds. However, as the slow repair of the cis-platinum-induced interstrand and DNA-protein cross-links leads to a certain persistency of these adducts, the unrepaired lesions might be responsible for cytotoxicity, mutagenicity, and antitumor activity. This indicates discriminating properties of the repair systems for certain cis-or trans-platinum-DNA adducts. The sister chromatid exchange induction seems to be related to the persistent DNA interstrand cross-links.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP16893053	cis-Diamminetetrachloroplatinum(IV)		16893-05-3	Price
AP16893064	trans-Diamminetetrachloroplatinum(IV)		16893-06-4	Price

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